1. Field of the Invention
This invention is applicable in all fields of medicine, but more particularly, in the specialties of anesthesiology, neurology, neurosurgery, internal medicine, pediatrics, oncology, obstetrics, neo-natology, cardiology, cardiac surgery, radiology, critical care medicine and transplantation in general. It relates to the use of exogenous taurine, homotaurine or methionine either alone or in various combinations but generally including taurine to induce analgesia or even anesthesia, or to protect organs in general and particularly the central nervous system (CNS) in patients (in-vivo conditions), or explanted donor organs (including but not limited to the liver, pancreas, small bowel, lungs, kidneys or the heart) (in vitro conditions) to be used for transplantation from the ravaging effects of hypoxia or ischemia (lack of or decreased oxygenation or blood flow) caused by vascular severance, such as during organ harvesting for transplantation, primary or secondary intra-vascular obstructions (such as in stroke) or extra-vascular factors accompanying trauma to the tissue (head trauma or during neurosurgical procedures).
2. Conventional Art
CNS ischemia is characterized by a complex cascade of hemodynamic, electrophysiological and biochemical processes with many interwoven vicious circles. The decrease of CNS blood flow below a critical threshold results in energy failure, tissue acidosis, disturbed ion homeostasis characterized by enhanced cellular K.sup.+ efflux and Na.sup.+ and Ca.sup.++ influx, membrane depolarization and cytotoxic edema (Choi, 1990; Rudolphi, 1992; Wieloch, 1982). These basic biochemical processes of ischemia might be quantitatively different in various organs but are qualitatively common to practically all tissues, and therefore general principles aimed to prevent or ameliorate them could be extended to organs other than the CNS.
In the CNS it has been reported that extracellular or interstitial levels of the excitatory aminoacids (EAAs) as well as inhibitory and potentially protective aminoacids such as taurine increase 4-20 fold during or shortly after ischemic injury (Benveniste, 1984; Hillered, 1989; Simpson, 1992) or head trauma (Nilsson, 1990; Persson, 1992); likewise there is a similar outpour of adenosine (Nilsson, 1990; Van Wylen, 1986). The flooding of the extracellular space with EAAs results in indiscriminate and continuous activation of postsynaptic EAAs receptors (phenomenon known as excitotoxicity) such as those for NMDA (N-methyl-D-aspartate, activated by glutamate and aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and KA (kainate) which may result in ultimate cell death, an occurrence that may be delayed for 2 or 3 days or even longer. This elevation of (interstitial) extracellular EAAs levels is thought to be part of the periphenomena of most acute CNS injury events leading to cell damage (Choi, 1990; DeLeo, 1987; Rothman, 1986). Even though the exact physiopathologic role glycine plays is not fully known, for NMDA receptors to become fully activated seems to require the presence of glycine in addition to the EAAs (glutamate or aspartate) (Johnson, 1987).
The role and importance of adenosine receptors in general and particularly in the CNS have been recently reviewed by Fredholm (1995) and Jacobson (1995). The neuroprotective role of adenosine in cerebral ischemia have been summarized by Choi (1990), Rudolphi (1992) and Schubert (1993).
Purinergic compounds which may interact with these adenosine receptors include the naturally present adenosine and adenosine tri-phosphate (ATP) or the synthetic adenosine analogues, and are well known to exert multiple functions in almost every tissue of the body, but are particularly conspicuous and therefore have been extensively studied in the brain where general antinociceptive (analgesic or even anesthetic), antiepileptic and tissue protective effects are well documented. Even though all the mechanisms of action of adenosine are not completely elucidated, the general consensus, as has been reviewed and summarized by Fredholm (1995) is that the effects are mediated by receptors of mainly the A1 (considered to be sensitive to .mu.molar concentrations of adenosine and functionally to produce hyperpolarization of membranes and inhibition of the release of EAAs) and A2 types, (sensitive to mmolar concentrations, and functionally characterized to produce release rather than inhibition of EAAs on one hand but particularly dilatation of the vasculature) located in cell membranes on the cell surface. In the CNS, although there are areas rich in A2 type receptors, A1 are predominant (Fredholm, 1995; Jacobson, 1995), and consequently their activation induce mostly widespread inhibition of the release of EAAs.
Pharmacological manipulation of these adenosine effects has been described as adenosinergic approach, and may include the administration of adenosine itself or ATP, or metabolically stable synthetic adenosine analogues, or therapy directed to increasing tissular adenosine concentration either by inhibiting its reuptake by the cells, or by inhibiting the destruction of the endogenously formed adenosine, or by the administration of precursors or prodrugs of adenosine to enhance its endogenous production.
The exogenous administration of purinergic compounds (adenosine or its analogues and ATP) that act on the adenosine receptors or pharmacological agents that alter the tissue levels of endogenous adenosine have been proven to have important antinociceptive: sedative, analgesic (Fukunaga, 1995; Sollevi, 1992), antiepileptic and/or neuroprotective activities (Fredholm, 1995; Rudolphi, 1992, Schubert, 1993). Because the extent of protection obtained with adenosinergic approaches in experimentally induced ischemia conditions of the CNS and other tissues, seems to be dose-dependent (Goldberg, 1988), in seeking significant A1 receptors effects, the administration of sufficient adenosinergic agents will almost always result in A2 receptors activation (dangerous levels of hypotension) and these consequent cardiovascular effects have hindered the acceptance of the adenosinergic approach at any clinical level (anesthesia, neurology or transplantation field) (Rudolphi, 1992).
In spite of the extensive work and considerable knowledge gained on the physiology and pharmacology of the various adenosine receptors as well as the adenosine analogues which were developed with the idea of selectively activating A1 receptors at small adenosine concentrations, to avoid the cardiovascular (vasodilating) hypotensive effects, which are mainly the result of A2 receptors activation that occurs at greater concentrations, many of the adenosinergic approaches affect both types of the ubiquitous and widely distributed adenosine receptors (throughout the entire body). Consequently their use has been hampered mainly by the undesirable cardiovascular effects, i.e., severe and dangerous decrease of blood pressure (hypotension) when dosages sufficient to attain adequate tissue levels at the target organ are used.
Until now, the beneficial CNS effects of adenosine and adenosinergic approaches in regards to antinociception and neuroprotection have been explained on the basis of the general effects of hyperpolarization of membranes and inhibition of the release of EAAs, effects that are thought to be mediated mainly by A1 type Adenosine receptors, but the inventors have further uncovered the heretofore non-described effect that adenosine releases in a dose-dependent manner various inhibitory aminoacids but mainly taurine, regardless of the area of the brain, whether rich in A1 or A2 receptors and therefore suggesting that such effects might not be mediated by the classic Adenosine receptors.
Although how taurine functions is not fully understood as yet, taurine is particularly abundant in the retina (where light promotes oxidation) and the brain (where oxidation might destroy the CNS function). Taurine is known to be a naturally present aminoacid with important anticalcic, antioxidant and protective features (Huxtable, 1980; Lehmann A., 1984; Wright C. E. 1986). Indeed, exogenously administered taurine in cats (van Gelder, 1972,a; 1976,b) as well as homotaurine in rats (Fariello, 1982) were reported previously to have antiepileptic effects but never found their way to be used as therapeutic agents. The common denominator of a number of protective pharmacological agents including barbiturates, benzodiazepines, isoflurane (all with anesthetic and anticonvulsant properties) and anticonvulsants (such as MK 801) is precisely the anticonvulsant action when used in therapeutically effective doses, and typically they induce marked EEG quiescence or functional depression (Kato, 1990; McDonald, 1990; Michenfelder [a], 1988). The inventors have further demonstrated that exogeneously administered taurine could mimic many if not all of the effects elicited by systemic administration of purinergic compounds, including those of anti-nociception with minimal or no cardiovascular effects.
The role of adenosine in pain perception as anti-nociceptive was summarized by Fredholm (1995). Of particular interest is the fact that the analgesic effects of morphine and morphine-like narcotics seem to be exerted via stimulation of adenosine release (Stone, 1981), and those of benzodiazepines via inhibition of adenosine uptake mechanisms. The administration of intravenous adenosine (Sollevi, 1992) or ATP (which is degraded to adenosine at the tissue level) proved to markedly decrease the requirements for anesthetic agents (Fukunaga, 1994) transoperatively, and notably the requirements for postoperative analgesics (Sollevi, 1992).